Ivermectin and the avermectin family, of which ivermectin is a member, is a series of new and very potent antiparasitic agents which are useful against a broad spectrum of endoparasites and ectoparasites in mammals as well as having agricultural uses against various parasites found in and on crops and in soil. Ivermectin is disclosed in U.S. Pat. No. 4,199,569, issued Apr. 22, 1980 to Chabala and Fisher. Ivermectin is a mixture, in the ratio of approximately 80:20 of 22,23-dihydro C-076 Bla and Blb. In administering ivermectin to animals it is very convenient to use parenteral formulations to administer the drug. While an aqueous micelle formulation (see U.S. Pat. No. 4,389,397) is useful for parenteral administration, higher activity has been observed against endoparasites than ectoparasites. It is known that ivermectin can be useful against ectoparasites and it is desireable to have a parenteral formulation with high levels of both endoand ectoparasiticidal activity.
Thus, it is desirable to prepare a parenteral liquid formulation of ivermectin which has activity against internal and external parasites. Ivermectin has very poor solubility in water, at a level of about 0.005 mg per ml at room temperature, but is very soluble in many organic solvents.
It was unexpectedly discovered during the investigation of the instant organic parenteral formulations that both endo- and ectoparasiticidal activity was observed which was not observed with the aqueous micelle formulation.
Ivermectin is a member of a family of compounds identified as avermectins. The basic avermectin compounds are isolated from the fermentation broth of the microorganism Streptomyces avermitilis. Such compounds are described in U.S. Pat. No. 4,310,519. In addition, certain derivatives of these basic fermentation products have been prepared.
Some of the avermectins contain a 22,23-double bond. This may be selectively reduced to prepare the ivermectin compounds discussed above. In addition, the avermectins possess a disaccharide moiety at the 13-position consisting of the a-L-oleandrosyl-a-L-oleandrosyl group. One or both of these saccharide groups may be removed as described in U.S. Pat. No. 4,206,205. The thus produced aglycone derivatives have a hydroxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in U.S. Pats. Nos. 4,171,314 and 4,173,571. On the avermectin compounds and derivatives are several hydroxy groups which may be acylated as described in U.S. Pat. No. 4,201,861.
It is anticipated that the process and formulation of the instant invention can be carried out on the foregoing compounds since all such compounds share to an only slightly varying degree, the spectrum of biological activity of the ivermectin compound.
In addition, a series of compounds identified as milbemycin compounds have the same 16 membered macrocyclic ring as do the avermectin compounds, although they do not have the disaccharide moiety and also differ in the nature of other substituent groups. These compounds are disclosed in U.S. Pat. No. 3,950,360 and they also would be expected to benefit in their spectrum of activity by the instant process and formulations.